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Molecular basis of Aquaporin-7 permeability regulation by pH

Mósca, Andreia F., De Almeida, Andreia ORCID:, Wragg, Darren, Martins, Ana P., Sabir, Farzana, Leoni, Stefano ORCID:, Moura, Teresa F., Prista, Catarina, Casini, Angela ORCID: and Soveral, Graça 2018. Molecular basis of Aquaporin-7 permeability regulation by pH. Cells 7 (11) , 207. 10.3390/cells7110207

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The aquaglyceroporin AQP7, a family member of aquaporin membrane channels, facilitates the permeation of water and glycerol through cell membranes and is crucial for body lipid and energy homeostasis. Regulation of glycerol permeability via AQP7 is considered a promising therapeutic strategy towards fat-related metabolic complications. Here, we used a yeast aqy-null strain for heterologous expression and functional analysis of human AQP7 and investigated its regulation by pH. Using a combination of in vitro and in silico approaches, we found that AQP7 changes from fully permeable to virtually closed at acidic pH, and that Tyr135 and His165 facing the extracellular environment are crucial residues for channel permeability. Moreover, instead of reducing the pore size, the protonation of key residues changes AQP7’s protein surface electrostatic charges, which, in turn, may decrease glycerol’s binding affinity to the pore, resulting in decreased permeability. In addition, since some pH-sensitive residues are located at the monomer-monomer interface, decreased permeability may result from cooperativity between AQP7’s monomers. Considering the importance of glycerol permeation via AQP7 in multiple pathophysiological conditions, this mechanism of hAQP7 pH-regulation may help the design of selective modulators targeting aquaglyceroporin-related disorders.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Advanced Research Computing @ Cardiff (ARCCA)
Additional Information: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited
Publisher: MDPI
ISSN: 2073-4409
Date of First Compliant Deposit: 15 November 2018
Date of Acceptance: 7 November 2018
Last Modified: 14 May 2023 16:53

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